Development of an objective, standardized tool for surgical assessment of deceased donor kidneys: the Cambridge Kidney Assessment Tool

Quality assessment in kidney transplantation involves inspection to identify negative markers of organ quality. However, there is a paucity of evidence guiding surgical appraisal, and currently there is no evidence to differentiate important features from those that can be safely ignored. We propose a method to standardize surgical assessment and derived a simple rule to rapidly identify kidneys suitable for transplantation. Donor and recipient data were recorded alongside clinical outcomes in a prospectively maintained database. We developed a proforma (Cambridge Kidney Assessment Tool, CKAT) and used it to assess deceased donor kidney transplants. Factors predictive of utilization were identified by multivariate and univariate logistic regression analysis of CKAT-assessment scores, and test performance was evaluated using standard 2 × 2 contingency tables. Ninety-seven kidneys were included at a single center (2013-2014), and 184 CKAT assessments were performed. A CKAT threshold of “Carrell + Perfusion >3” was highly specific (99%) and performed favorably to consultant opinion (specificity 95%). 96% of the kidneys implanted in accordance with the rule survived to 1 year (mean eGFR 45.3 mL/min/1.73 m2). To our knowledge, this is the first attempt to objectively define macroscopic features that are relevant to kidney utilization. Common language could support training in organ assessment and ultimately help address unnecessary discard of donor kidneys

Utilization and Outcomes of Single and Dual Kidney Transplants from Older Deceased Donors in the United Kingdom

BACKGROUND AND OBJECTIVES: Kidneys from elderly deceased donors are often discarded after procurement if the expected outcomes from single kidney transplantation are considered unacceptable. An alternative is to consider them for dual kidney transplantation. We aimed to examine the utilization of kidneys from donors aged ≥60 years in the United Kingdom and compare clinical outcomes of dual versus single kidney transplant recipients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data from the United Kingdom Transplant Registry from 2005 to 2017 were analyzed. We examined utilization rates of kidneys retrieved from deceased donors aged ≥60 years, and 5-year patient and death-censored graft survival of recipients of dual and single kidney transplants. Secondary outcomes included eGFR. Multivariable analyses and propensity score analysis were used to correct for differences between the groups. RESULTS: During the study period, 7841 kidneys were procured from deceased donors aged ≥60 years, of which 1338 (17%) were discarded; 356 dual and 5032 single kidneys were transplanted. Donors of dual transplants were older (median, 73 versus 66 years; P<0.001) and had higher United States Kidney Donor Risk Indices (2.48 versus 1.98; P<0.001). Recipients of dual transplants were also older (64 versus 61 years; P<0.001) and had less favorable human leukocyte antigen matching (P<0.001). After adjusting for confounders, dual and single transplants had similar 5-year graft survival (hazard ratio, 0.81; 95% CI, 0.59 to 1.12). No difference in patient survival was demonstrated. Similar findings were observed in a matched cohort with a propensity score analysis method. Median 12-month eGFR was significantly higher in the dual kidney transplant group (40 versus 36 ml/min per 1.73 m(2); P<0.001). CONCLUSIONS: Recipients of kidneys from donors aged ≥60 years have similar 5-year graft survival and better graft function at 12 months with dual compared with single deceased donor kidney transplants

A systematic review of living kidney donor enhanced recovery after surgery.

Enhanced recovery after surgery (ERAS) reduces complications and shortens hospital stay without increasing readmission or mortality. However, its role in living donor nephrectomy (LDN) has not yet been defined. Medline, Embase, CINAHL, PsycINFO, and Cochrane Central were searched prior to 08/01/21 for all randomized controlled and cohort studies comparing ERAS to standard of care in LDN. The study was registered on PROSPERO (CRD: CRD42019141706). One thousand, three hundred seventy-seven patients were identified from 14 studies (698 patients with ERAS and 679 patients without). There were considerable differences in the protocols used, and compliance with general ERAS recommendations was poor. Meta-analysis of laparoscopic procedures (including hand- and robot-assisted) revealed that duration of stay was significantly reduced by 0.98 days with ERAS (95% CI = 0.36-1.60, P = .002) and opiate requirement by 32.4 mg (95% CI = 1.1-63.7, P = .04). There was no significant difference n readmission rates or complications. Quality of evidence was low to moderate assessed using the GRADE tool. This review suggests there is a positive benefit of ERAS in laparoscopic LDN. However, there was considerable variation in ERAS protocols used, and the quality of evidence was low; as such, a guideline for ERAS in LDN should be developed and validated

Low Carb Program health app within a hospital-based obesity setting : cluster randomised service evaluation

Background: Obesity underlies much chronic disease. Digitalization of obesity management provides an opportunity to innovate our traditional model of health care delivery within this setting, and to transform its scalability potentially to the population level. Objective: The objective was to assess the feasibility and effectiveness of the Low Carb Program app for weight loss, applied within our hospital-based (tier 3) obesity service. Due to the disrupting effects of the COVID-19 pandemic on our obesity service, we compared the clinical outcomes from the Low Carb Program app applied in the context of remote patient appointments over the telephone with the prepandemic traditional standard of care. Methods: We invited patients who attended our hospital-based obesity service to engage with the Low Carb Program smartphone app. We combined this approach with remote delivery (over the telephone) of obesity management from medical and psychology members of our obesity team during the COVID-19 pandemic. Outcome variables included changes in body weight and changes in HbA1c as a marker of glycemic control. We compared data from the Low Carb Program group with a retrospective control group (n=126) that had received traditional face-to-face obesity management from our team without concomitant use of the Low Carb Program app in the pre–COVID-19 era. T test comparisons were employed, with P<.05 considered significant. Results: The mean weight of participants (n=105) was 130.2 kg, with 59% (n=62) females and a mean age of 48.8 years. Most participants (90/105, 86%) completed the Low Carb Program app registration process and engaged with the Low Carb Program app program; at follow-up, most participants (88/105, 84%) had actively engaged with the Low Carb Program app within the prior 30 days. The majority of participants (58/105, 55%) self-reported outcomes within the app. Mean duration of clinical follow-up for recruited participants who received the app was 7.4 months. Paired data were available for 48 participants for body weight and 41 participants for HbA1c. Paired sample t test analysis revealed a statistically significant mean loss of body weight of 2.7 kg (P=.001) and improvement in HbA1c of 3.3 mmol/mol (P=.01). The mean weight of control group patients (n=126) was 137.1 kg, with 74% (93/126) females and a mean age of 44.4 years. The mean follow-up for this group was 6 months. Data comparisons between the app user group and the pre–COVID-19 retrospective control group revealed equivalence for loss of body weight and change in HbA1c between the two groups. Conclusions: We provide evidence to support the feasibility of implementing the Low Carb Program app combined with remote management; this is the first proof of concept for digitalized management within a hospital-based (tier 3) obesity service. We demonstrate the potential clinical efficacy of the approach in terms of improvements in body weight and glycemic control

Transplantation of organs from deceased donors with meningitis and encephalitis: a UK registry analysis.

BACKGROUND: Deceased organ donors, where the cause of death is meningitis or encephalitis, are a potential concern because of the risks of transmission of a potentially fatal infection to recipients. METHODS: Using the UK Transplant Registry, a retrospective cohort analysis of deceased organ donors in the UK was undertaken to better understand the extent to which organs from deceased donors with meningitis and/or encephalitis (M/E) (of both known and unknown cause) have been used for transplantation, and to determine the associated recipient outcomes. RESULTS: Between 2003 and 2015, 258 deceased donors with M/E were identified and the causative agent was known in 188 (72.9%). These donors provided 899 solid organs for transplantation (455 kidneys and 444 other organs). The only recorded case of disease transmission was from a donor with encephalitis of unknown cause at time of transplantation who transmitted a fatal nematode infection to 2 kidney transplant recipients. A further 3 patients (2 liver and 1 heart recipient) died within 30 days of transplantation from a neurological cause (cerebrovascular accident) with no suggestion of disease transmission. Overall, patient and graft survival in recipients of organs from donors with M/E were similar to those for all other types of deceased organ donor. CONCLUSION: Donors dying with M/E represent a valuable source of organs for transplantation. The risk of disease transmission is low but, where the causative agent is unknown, caution is required.National Institute of Health Research, Blood and Transplant Research Unit (NIHR BTRU) on Organ Donation and Transplantation at the University of Cambridge in collaboration with Newcastle University and in partnership with NHS Blood and Transplant (NHSBT), and the NIHR Cambridge Biomedical Research CentreThis is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1111/tid.1262

Deceased Organ Donors With a History of Increased Risk Behavior for the Transmission of Blood-Borne Viral Infection: The UK Experience.

BACKGROUND: Deceased organ donors are routinely screened for behaviors that increase the risk of transmissible blood-borne viral (BBV) infection, but the impact of this information on organ donation and transplant outcome is not well documented. Our aim was to establish the impact of such behavior on organ donation and utilization, as well transplant recipient outcomes. METHODS: We identified all UK deceased organ donors from 2003 to 2015 with a disclosed history of increased risk behavior (IRB) including intravenous drug use (IVDU), imprisonment and increased risk sexual behavior. RESULTS: Of 17 262 potential donors, 659 (3.8%) had IRB for BBV and 285 (1.7%) were seropositive for BBV, of whom half had a history of IRB (mostly IVDU [78.5%]). Of actual donors with IRB, 393 were seronegative for viral markers at time of donation. A history of recent IVDU was associated with fewer potential donors proceeding to become actual organ donors (64% vs 75%, P = 0.007). Donors with IRB provided 1091 organs for transplantation (624 kidneys and 467 other organs). Transplant outcome was similar in recipients of organs from donors with and without IRB. There were 3 cases of unexpected hepatitis C virus transmission, all from an active IVDU donor who was hepatitis C virus seronegative at time of donation, but was found to be viremic on retrospective testing. CONCLUSIONS: Donors with a history of IRB provide a valuable source of organs for transplantation with good transplant outcomes and there is scope for increasing the use of organs from such donors.The National Institute of Health Research, Blood and Transplant Research Unit (NIHR BTRU) on Organ Donation and Transplantation at the University of Cambridge in collaboration with Newcastle University and in partnership funded this research with NHS Blood and Transplant (NHSBT)

PreImplantation Trial of Histopathology In renal Allografts (PITHIA): a stepped-wedge cluster randomised controlled trial protocol.

INTRODUCTION: Most potential kidney transplant donors in the UK are aged over 60 years, yet increasing donor age is associated with poorer graft survival and function. Urgent preimplantation kidney biopsy can identify chronic injury, and may aid selection of better 'quality' kidneys from this group. However, the impact of biopsy on transplant numbers remains unproven. The PreImplantation Trial of Histopathology In renal Allografts (PITHIA) study will assess whether the introduction of a national, 24 hours, digital histopathology service increases the number, and improves outcomes, of kidneys transplanted in the UK from older deceased donors. METHODS AND ANALYSIS: PITHIA is an open, multicentre, stepped-wedge cluster randomised study, involving all UK adult kidney transplant centres. At 4-monthly intervals, a group of 4-5 randomly selected clusters (transplant centres) will be given access to remote, urgent, digital histopathology (total intervention period, 24 months). The trial has two primary end points: it is powered for an 11% increase in the proportion of primary kidney offers from deceased donors aged over 60 years that are transplanted, and a 6 mL/min increase in the estimated glomerular filtration rate of recipients at 12 months post-transplant. This would equate to an additional 120 kidney transplants performed in the UK annually. Trial outcome data will be collected centrally via the UK Transplant Registry held by NHS Blood and Transplant (NHSBT) and will be analysed using mixed effects models allowing for clustering within centres and adjusting for secular trends. An accompanying economic evaluation will estimate the cost-effectiveness of the service to the National Health Service. ETHICS AND DISSEMINATION: The study has been given favourable ethical opinion by the Cambridge South Research Ethics Committee and is approved by the Health Research Authority. We will present our findings at key transplant meetings, publish results within 4 years of the trial commencing and support volunteers at renal patient groups to disseminate the trial outcome. TRIAL REGISTRATION NUMBER: ISRCTN11708741; Pre-results.nih

Adrenoceptors in GtoPdb v.2021.3

The nomenclature of the Adrenoceptors has been agreed by the NC-IUPHAR Subcommittee on Adrenoceptors [60, 186]. Adrenoceptors, &#945;1 The three &#945;1-adrenoceptor subtypes &#945;1A, &#945;1B and &#945;1D are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. -(-)phenylephrine, methoxamine and cirazoline are agonists and prazosin and doxazosin antagonists considered selective for &#945;1- relative to &#945;2-adrenoceptors. [3H]prazosin and [125I]HEAT (BE2254) are relatively selective radioligands. S(+)-niguldipine also has high affinity for L-type Ca2+ channels. Fluorescent derivatives of prazosin (Bodipy FLprazosin- QAPB) are used to examine cellular localisation of &#945;1-adrenoceptors. &#945;1-Adrenoceptor agonists are used as nasal decongestants; antagonists to treat symptoms of benign prostatic hyperplasia (alfuzosin, doxazosin, terazosin, tamsulosin and silodosin, with the last two compounds being &#945;1A-adrenoceptor selective and claiming to relax bladder neck tone with less hypotension); and to a lesser extent hypertension (doxazosin, terazosin). The &#945;1- and &#946;2-adrenoceptor antagonist carvedilol is used to treat congestive heart failure, although the contribution of &#945;1-adrenoceptor blockade to the therapeutic effect is unclear. Several anti-depressants and anti-psychotic drugs are &#945;1-adrenoceptor antagonists contributing to side effects such as orthostatic hypotension. Adrenoceptors, &#945;2 The three &#945;2-adrenoceptor subtypes &#945;2A, &#945;2B and &#945;2C are activated by (-)-adrenaline and with lower potency by (-)-noradrenaline. brimonidine and talipexole are agonists and rauwolscine and yohimbine antagonists selective for &#945;2- relative to &#945;1-adrenoceptors. [3H]rauwolscine, [3H]brimonidine and [3H]RX821002 are relatively selective radioligands. There are species variations in the pharmacology of the &#945;2A-adrenoceptor. Multiple mutations of &#945;2-adrenoceptors have been described, some associated with alterations in function. Presynaptic &#945;2-adrenoceptors regulate many functions in the nervous system. The &#945;2-adrenoceptor agonists clonidine, guanabenz and brimonidine affect central baroreflex control (hypotension and bradycardia), induce hypnotic effects and analgesia, and modulate seizure activity and platelet aggregation. clonidine is an anti-hypertensive (relatively little used) and counteracts opioid withdrawal. dexmedetomidine (also xylazine) is increasingly used as a sedative and analgesic in human [31] and veterinary medicine and has sympatholytic and anxiolytic properties. The &#945;2-adrenoceptor antagonist mirtazapine is used as an anti-depressant. The &#945;2B subtype appears to be involved in neurotransmission in the spinal cord and &#945;2C in regulating catecholamine release from adrenal chromaffin cells. Although subtype-selective antagonists have been developed, none are used clinically and they remain experimental tools. Adrenoceptors, &#946; The three &#946;-adrenoceptor subtypes &#946;1, &#946;2 and &#946;3 are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. Isoprenaline is selective for &#946;-adrenoceptors relative to &#945;1- and &#945;2-adrenoceptors, while propranolol (pKi 8.2-9.2) and cyanopindolol (pKi 10.0-11.0) are relatively selective antagonists for &#946;1- and &#946;2- relative to &#946;3-adrenoceptors. (-)-noradrenaline, xamoterol and (-)-Ro 363 show selectivity for &#946;1- relative to &#946;2-adrenoceptors. Pharmacological differences exist between human and mouse &#946;3-adrenoceptors, and the 'rodent selective' agonists BRL 37344 and CL316243 have low efficacy at the human &#946;3-adrenoceptor whereas CGP 12177 (low potency) and L 755507 activate human &#946;3-adrenoceptors [88]. &#946;3-Adrenoceptors are resistant to blockade by propranolol, but can be blocked by high concentrations of bupranolol. SR59230A has reasonably high affinity at &#946;3-adrenoceptors, but does not discriminate between the three &#946;- subtypes [320] whereas L-748337 is more selective. [125I]-cyanopindolol, [125I]-hydroxy benzylpindolol and [3H]-alprenolol are high affinity radioligands that label &#946;1- and &#946;2- adrenoceptors and &#946;3-adrenoceptors can be labelled with higher concentrations (nM) of [125I]-cyanopindolol together with &#946;1- and &#946;2-adrenoceptor antagonists. Fluorescent ligands such as BODIPY-TMR-CGP12177 can be used to track &#946;-adrenoceptors at the cellular level [8]. Somewhat selective &#946;1-adrenoceptor agonists (denopamine, dobutamine) are used short term to treat cardiogenic shock but, chronically, reduce survival. &#946;1-Adrenoceptor-preferring antagonists are used to treat cardiac arrhythmias (atenolol, bisoprolol, esmolol) and cardiac failure (metoprolol, nebivolol) but also in combination with other treatments to treat hypertension (atenolol, betaxolol, bisoprolol, metoprolol and nebivolol) [507]. Cardiac failure is also treated with carvedilol that blocks &#946;1- and &#946;2-adrenoceptors, as well as &#945;1-adrenoceptors. Short (salbutamol, terbutaline) and long (formoterol, salmeterol) acting &#946;2-adrenoceptor-selective agonists are powerful bronchodilators used to treat respiratory disorders. Many first generation &#946;-adrenoceptor antagonists (propranolol) block both &#946;1- and &#946;2-adrenoceptors and there are no &#946;2-adrenoceptor-selective antagonists used therapeutically. The &#946;3-adrenoceptor agonist mirabegron is used to control overactive bladder syndrome. There is evidence to suggest that &#946;-adrenoceptor antagonists can reduce metastasis in certain types of cancer [189]